Editorial
New therapeutic approaches in type 2 diabetes mellitus
Nuevos planteamientos terapéuticos en la diabetes mellitus tipo 2
Carles Zafon
Unidad de Investigación en Diabetes y Metabolismo, Servicio de Endocrinología y Nutrición, Hospital Universitari Vall d’Hebron, Instituto de Investigación Vall d’Hebron (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
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"documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Clin. 2015;145:482-4" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1 "HTML" => 1 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial article</span>" "titulo" => "Hip fracture incidence in Spain" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "482" "paginaFinal" => "484" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Incidencia de la fractura de cadera en España" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Íñigo Etxebarria-Foronda" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Íñigo" "apellidos" => "Etxebarria-Foronda" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775315002213" "doi" => "10.1016/j.medcli.2015.04.009" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775315002213?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616300249?idApp=UINPBA00004N" "url" => "/23870206/0000014500000011/v1_201604300039/S2387020616300249/v1_201604300039/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "New therapeutic approaches in type 2 diabetes mellitus" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "485" "paginaFinal" => "487" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Carles Zafon" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Carles" "apellidos" => "Zafon" "email" => array:1 [ 0 => "26276czl@comb.cat" ] ] ] "afiliaciones" => array:2 [ 0 => array:2 [ "entidad" => "Unidad de Investigación en Diabetes y Metabolismo, Servicio de Endocrinología y Nutrición, Hospital Universitari Vall d’Hebron, Instituto de Investigación Vall d’Hebron (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain" "identificador" => "aff0005" ] 1 => array:2 [ "entidad" => "Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain" "identificador" => "aff0010" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nuevos planteamientos terapéuticos en la diabetes mellitus tipo 2" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Current medicine's priority is to customize the therapeutic approach, shifting the focus from illness to the patient. This view is even more evident in chronic diseases, in which the biography can modulate the needs of people affected over the years. Diabetes mellitus type 2 (DM2) is a paradigm of the new approach and thus is collected in the latest guidelines and consensus documents.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">1,2</span></a> Thus, therapeutic algorithms have been losing their “vertical” therapeutic scaling in multi-step proposal for a single drug in each step, to win a “horizontal” character, in which all therapeutic options are valid depending on the specific characteristics of the patient we are dealing with. On the other hand, in recent years, new therapeutic families have appeared with actions that differ from the classic hypoglycemic agents used to date. This has led to having to consider the choice of the most appropriate drug at all times, choosing between an increasingly diverse number of options. Faced with this new scenario, when a modification of the treatment regimen is decided, whether it involves the association of a new drug, or replacing the current one with another, the physician must consider a number of issues so that, depending on the response, choose the most suitable.</p><p id="par0010" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Mechanism of action</span>. T2DM is characterized mainly by the presence of resistance to insulin action associated with progressive loss of the pancreatic beta-cell capacity for producing the said hormone. However, other alterations that can be used as therapeutic avenues have been identified in recent years. Currently we have different families of drugs with different mechanisms of action.<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">3,4</span></a> Thus, we have the most classic and consolidated, such as metformin, which improves insulin resistance, sulfonylurea (SUs) and glinides, which increase pancreatic insulin production, alpha-glucosidase inhibitors, which decrease the absorption of carbohydrates in the digestive tract, and pioglitazone, which increases sensitivity to hormone action. We have added incretin-based drugs to the therapeutic arsenal and, more recently, the <span class="elsevierStyleItalic">sodium-glucose cotransporter 2</span> inhibitors (SGLT-2). In turn, incretin-based drugs can be divided into dipeptidyl peptidase-4 inhibitors (DPP-4) and <span class="elsevierStyleItalic">glucagon-like peptide-1</span> analogs (GLP-1). The first block the action of the DPP-4 enzyme, responsible for disabling GLP-1, thereby increasing the half-life and, subsequently, the action of the said hormone of the gastrointestinal system. The GLP-1 analogs are molecules with an action similar to that of GLP-1, but with greater potency and longer effect. For their part, the SGLT-2 inhibitors block the renal reabsorption of glucose, resulting in a “drug glycosuria” that leads to an improvement of glycemic control. The possibility of acting on a growing number of mechanisms allows to choose the most appropriate drug or combination of drugs.</p><p id="par0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Level of metabolic control</span>. There is a direct relationship between the levels of glycated hemoglobin (HbA<span class="elsevierStyleInf">1c</span>) and the risk of chronic complications.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">5</span></a> A 7% target has been established as a criterion for good control. However, in certain groups of patients different HbA<span class="elsevierStyleInf">1c</span> values are advised.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">6</span></a> So, when choosing a drug, it is fitting to assess both the degree of decrease in HbA<span class="elsevierStyleInf">1c</span> achieved with such a treatment as well as the pursued objective.</p><p id="par0020" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Effect on chronic complications</span>. Beyond reducing the risk of chronic complications with the metabolic control of the disease, several studies have attempted to analyze the intrinsic effect of different therapeutic options. The UKPDS showed that both metformin and SUs reduced the risk of microvascular complications, but only the first showed its effectiveness in macrovascular complications.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">7</span></a> In addition, metformin reduces the risk of all-cause mortality.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">8</span></a> The efficacy of new drugs in this aspect has not yet been demonstrated, more years must pass in order to assess their impact.</p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Effect on cardiovascular risk</span>. From the studies carried out in the Framingham cohort it has been established that diabetes mellitus multiplies by two to four times the risk of suffering a cardiovascular (CV)<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">9</span></a> event. In addition, the disease is often associated with a set of other disorders that are, all of them, cardiovascular risk factors such as hypertension or dyslipidemia. Therefore, patients with DM2 present extreme CV risk. This has led to analyze whether the drugs used in its treatment add intrinsically an unfavorable CV profile. To date, metformin is the only one that has been shown to reduce the risk significantly. The risk factor contribution of most incretin-based drugs and SGLT-2 inhibitors is not known, although they seem to indicate a neutral effect.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">10</span></a> Insulin therapy does not appear to increase CV risk.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">11</span></a> SUs deserve a special mention. For many years it has been raised that this group could increase the risk of adverse events. Although the evidence is not entirely conclusive and the risk is not the same for all the drugs within this family, several retrospective studies and a meta-analysis seem to corroborate their harmful profile.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">12,13</span></a> This phenomenon could be related to two effects: increased risk of hypoglycemia and modification in the myocardial tissue's response to anoxia, a phenomenon known as cardiac preconditioning.</p><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Side effects</span>. As it happens with the indication of any drug, before modifying a regimen in a patient with type 2 diabetes, the side effects need to be considered. The specific effects of each family and the hypoglycemic treatment own effects should be assessed. In the latter case, the 2 most common side effects are hypoglycemia and weight gain. Hypoglycemia is, undoubtedly, one of them major problems when treating diabetes mellitus.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">14</span></a> Metformin, pioglitazone, incretin-based drugs, acarbose inhibitors, DPP-4 inhibitors and SGLT-2 inhibitors have a very low risk, in some cases a null risk. SUs, to a lesser extent repaglinide and insulin, are the drugs that have a higher risk. In fact, hypoglycemia is the great Achilles heel of the SUs and, as mentioned earlier, this effect could be related to the increased cardiovascular risk of this group of drugs. Thus, before a new prescription, it is necessary to assess whether the risk of hypoglycemia is particularly serious in that particular patient (elderly, polypharmacy or risk profession, among others). Weight gain is another factor intrinsically associated with the treatment of type 2 diabetes, although its clinical significance is less than in the case of hypoglycemia. In this aspect, insulin, SU, repaglinide and pioglitazone are the drugs that determine the most significant weight increase. Metformin and DPP-4 inhibitors show a neutral profile, whereas the SGLT-2 inhibitors, and to a greater extent, the GLP-1 analogs, are associated with significant weight loss, therefore, their highest indication will be in patients with type 2 diabetes and obesity.</p><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Contraindications</span>. Each drug family has its specific contraindications, which must be evaluated before prescription. One of the most frequent complications of the disease is renal involvement. In addition, other comorbidities, such as hypertension or peripheral artery disease, may also contribute to kidney function failure. Most drugs are eliminated through this organ. Given all this, different degrees of renal impairment have been established as a limit in order to use them.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">15</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Economic cost</span>. Another aspect to be taken into account when prescribing a new drug is its cost. New treatments of type 2 diabetes cost a lot more than the older treatments. So, if we take as reference the price of metformin, SUs only cost twice as much, while DPP-4 inhibitors cost 17 times as much, insulin analogs 5–18 times as much and GLP-1 analogs can cost 35–57 times more than biguanide.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">16</span></a> However, other economic aspects should be take into account beyond the drug cost itself. It has been established that this represents only 18% of the total cost of a patient with the disease.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">17</span></a> DM2 expenditure balances are complex to evaluate,<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">18</span></a> but for many of the new drugs, despite their high price, they have shown to be cost-effective.<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">19,20</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Shared decision making with the patient</span>. Last but not least, patient-centered medicine assumes that this one must participate and get involved in the whole process of the disease, treatment included.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">21</span></a> The patient should be fully informed of the right therapeutic alternatives, the pros and cons of their use and possible side effects. The adequacy of the best option with patient participation means a better acceptance of the treatment plan and greater adherence to it, aspects that ultimately improve disease control.</p><p id="par0050" class="elsevierStylePara elsevierViewall">So, we are facing a period of change in the way medicine and healthcare professionals face disease, with a special emphasis on the role that the patient should have. Diabetes, as a chronic and highly prevalent disease, should be an example in this new avenue of management. In recent years new therapeutic families that increase the range of treatment options for each stage of the disease have appeared, allowing us to choose the most appropriate drug or combination of drugs. In the election we must take into account not just purely medical aspects, but also consider the situation and opinion of the patient at that particular time. Algorithms and clinical practice guidelines point in this direction, leaving the door open for more treatment options when compared to the past decade. In the not too distant future we will be able to add new therapeutic options.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">22</span></a> Metabolic surgery is beginning to be considered as a possibility in some cases, although it is still far from demonstrating the full extent of its effectiveness.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">23</span></a> Pharmacogenomics is making its way and, in the not so distant future, it will also help us to choose the drug that offers the greatest effectiveness with minimal risk of side effects.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">24</span></a> However, despite all these changes, we must not forget that the best treatment for type 2 diabetes is its prevention with awareness programs and improvement in healthy lifestyles, and once established, before prescribing any drug, the dietary measures and lifestyle changes remain the first therapeutic step.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Zafon C. Nuevos planteamientos terapéuticos en la diabetes mellitus tipo 2. 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